Bosentan, represented by structural formula (I) and chemically named 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzene-sulfonamide is an endothelin receptor antagonist. It is used for the treatment of endothelin-receptor mediated disorders, in particular circulatory and cardiovascular disorders such as hypertension, ischemia, pulmonary hypertension, vasospasm and angina pectoris. The marketed product comprising bosentan, Tracleer®, is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with grade III functional status.

Bosentan (I) was first described in U.S. Pat. No. 5,292,740. The preparation method involves two steps (shown in Scheme 1) starting from the dichloro compound (1). The second reaction step is carried out in ethylene glycol with sodium metal used as the base at a temperature of 100-110° C. The process results in bosentan (I) of about 69-73% purity. The purity is further increased by column chromatography, however, this reduces the yield such that the overall yield of bosentan (I) from the dichloro compound (1) is only about 30-40%. Further, use of sodium metal has disadvantages. Apart from being inconvenient to handle due to moisture sensitivity, sodium metal is also a safety hazard during handling, storage and quenching.

One of the problems to be overcome in the preparation of bosentan (I) is the formation of the undesired ethylene glycol bis-sulfonamide dimer of formula (II) in which two molecules of the pyrimidine monohalide (2) are coupled with one molecule of ethylene glycol. The removal of this impurity requires costly and laborious separation steps. To minimize the formation of this impurity a large excess of ethylene glycol can be used. However, using a large excess of ethylene glycol is impractical on a large industrial scale, because ethylene glycol is toxic and its high boiling point means that its removal by distillation is energy and time consuming.

U.S. Pat. No. 6,136,971 discloses a process (shown in Scheme 2) for the preparation of bosentan with high purity (>99%) and solves the problem of the dimer formation by utilising a mono-protected 1,2-diheteroethylene anion. In a particularly preferred aspect, the protecting group is a tert-butyl group used to protect one hydroxyl group of ethylene glycol as an ether. The protecting group is then removed using formic acid to produce a formyloxy-protected ethylene glycol sulfonamide derivative (4). Treatment of this compound (4) with a base, preferably sodium hydroxide, then produces an ethylene glycol sulfonamide derivative, bosentan (I), containing a free hydroxy group. The skilled person will appreciate that such a process is laborious, as it involves a number of steps relating to the protection and deprotection of ethylene glycol as the tert-butyl ether. Consequently, the process is not suitable for commercial manufacture.

In view of the above disadvantages associated with the prior art, there is a need for an improved process for the preparation of bosentan which does not involve multiple steps and further eliminates the need for cumbersome purification techniques, is economical and high yielding, and which provides bosentan with a high degree of purity.
It has further been noted that the prior art processes need to employ high temperatures in the preparation of bosentan. This further adds to the inefficiency and high processing costs. The high temperatures also increase the likelihood of impurities being formed during manufacture. Thus there is also a need for a process wherein the temperatures employed during the manufacturing process are such as to avoid the prior art problems.